The skeletal response (bone biopsy) of patients with chronic renal disease to 25OHD3 therapy was quantitated both histologically and biochemically and compared to bone collagen-mineral maturation profiles and bone mineral content. Bone maturational profiles using collagen cross-linking and mineralization profiles proved to be much more sensitive indices of skeletal responsivity to therapy when compared to histomorphometric and chemical analyses. An analysis of the renal tubular handling of both glucose and phosphate in untreated patients with hypophosphatemic vitamin D-resistance rickets (VDRR) revealed a select population of individuals who developed severe hypophosphatemia and decreased renal reabsorption of filtered phosphate during high carbohydrate feeding. The data stress the need for careful screening of patients with VDRR with respect to dietary indiscretions and especially during periods of phosphate therapy. Studies in acidotic chicks demonstrated a decrease in the renal tubular uptake of 250HD, and accelerated mitochondrial conversion of 250HD to 1,25(OH)2D3 and an increased catabolism of 1,25(OH)2D3. The data are consistent with the "resistance" to vitamin D therapy observed in disorders of renal fuction characterized by a systemic acidosis and normal glomerular filtration rates. Studies in streptozotocin-induced diabetic rats revealed a significant decrease in bone appositional rates, hypercalcemia, a decrease in circulating parathyroid hormone and an increase in circulatingcorticosteroids. The data did not verify earlier hypothesis incriminating acquired defect(s) in vitamin D metabolism in the experimental diabetic state. The defects in calcium absorption and decreased bone mass in the diabetic rat can all be explained by a corticosteroid-excess syndrome.